Treatment of abnormal increases in gastrointestinal motility with (R)-verapamil

ABSTRACT

The present invention is directed to methods of treating, preventing, and/or managing abnormal increases in gastrointestinal motility, and intestinal conditions that cause the same. Such conditions include, but are not limited to, irritable bowel syndrome (IBS), infectious diseases of the small and large intestines, and symptoms of any of the foregoing. In particular, the present invention discloses methods of using (R)-verapamil, as well as compositions and formulations containing the same.

[0001] This application claims priority to U.S. Provisional PatentApplication No. 60/335,959, filed Nov. 15, 2001, the entire disclosureof which is incorporated herein by reference.

[0002] The present invention is generally directed to methods oftreating, preventing, and/or managing abnormal increases ingastrointestinal motility. Such abnormal increases may be caused by oneor more intestinal conditions, including, but not limited to, irritablebowel syndrome (IBS), infectious diseases of the small and largeintestine, and symptoms of any of the foregoing. In particular, theinvention relates to methods of treating, preventing, and/or managingabnormal increases in gastrointestinal motility with stereo-specificforms of calcium channel blockers, including but not limited to,(R)-verapamil.

[0003] Irritable Bowel Syndrome (IBS) results in about 3.5 millionphysician visits per year, and is the most common diagnosis made bygastroenterologists, accounting for about 25% of all patients diagnosed(Camilleri and Choi, Aliment Pharmacol. Ther., 11(1):3-15, 1997).Individuals afflicted with IBS visit doctors more frequently, enjoy alower quality of life, and miss work more often relative to those withno bowel symptoms (Drossman et al., Dig. Dis. Sci., 38:1569-1580, 1993).As a consequence, individuals suffering from IBS incur significantlyhigher health care costs than those without the condition (Talley etal., Gastroenterology, 109:1736-1741, 1995).

[0004] IBS is characterized by abdominal pain and altered bowel function(Mayer et al., Gastroenterology, 107:271-93, 1994; Camilleri and Choi,1997; Drossman et al., Am. J. Gastroent., 91:2270-81, 1996). Thecondition leads to crampy pain, gassiness, bloating, and changes inbowel habits. Some people with IBS have constipation (difficult orinfrequent bowel movements); others have diarrhea (frequent loosestools, often with an urgent need to move the bowels); and some peopleexperience both. Sometimes the person with IBS has a crampy urge to movethe bowels but cannot do so. See, e.g., NIH Publication No. 97-693,National Digestive Diseases Information Clearinghouse, NationalInstitute of Health, 1992 (also available on-line at“www.niddk.nih.gov/health/digest/pubs/irrbowel/irrbowel.htm” postedFebruary 1998, last updated November 2000).

[0005] Through the years, IBS has been called by many names-colitis,mucous colitis, spastic colon, spastic bowel, and functional boweldisease. Most of these terms are inaccurate. Id. Colitis, for instance,means inflammation of the large intestine (colon). IBS, however, doesnot cause inflammation and should not be confused with inflammatorybowel diseases, such as ulcerative colitis and Crohn's disease. Id.

[0006] IBS is a well-recognized clinical entity, but no causativeetiologic agents or structural or biochemical defects have beenpositively identified. In many patients, intraluminal contents exhibitunusually rapid transit through the length of the small intestine andcolon. Afflicted patients generally complain of abdominal discomfort andreport audible bowel noises, cramping and abdominal pain, an urgency todefecate, and the passage of loose stools often covered with mucus.

[0007] Due to the lack of readily identifiable structural or biochemicalabnormalities associated with IBS, the medical community has developed aconsensus definition and set of criteria known as the Manning or RomeCriteria, to aid in the diagnosis of IBS (Manning et al., Br. Med. J.,2:653-4, 1978; Thompson et al., Gastroent. Int., 2:92-5,1989). Accordingto the Rome criteria, IBS is identified by abdominal pain or discomfortwhich is relieved by defecation and/or associated with a change infrequency or consistency of stools, plus two or more of the following:altered stool frequency, altered stool form, altered stool passage,passage of mucus, and bloating or feeling of abdominal distention(Dalton and Drossman, Am. Fam. Physician, 55(3):875-880, 1997).

[0008] Despite increasing diagnosis, no effective treatments have beenidentified for intestinal conditions such as IBS. Thus, there exists astrong need in the art for new or more effective methods for treating,preventing, and/or managing intestinal conditions such as IBS.

[0009] Verapamil (benzeneacetonitrile;α-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-α-(1-methylethyl)hydrochloride) is a commercially available drug that, when used to treatcardiovascular conditions, acts as a calcium ion influx inhibitor byblocking calcium ion channels. The drug is typically prescribed as atreatment for cardiovascular conditions, such as hypertension, atrialfibrillation, angina, and paroxysmal supraventricular tachycardia. Thedrug is normally prescribed as a racemic mixture containingapproximately equal amounts of (R)-verapamil and (S)-verapamil.

[0010] The pharmacodynamics and pharmacokinetics of the (R) and (S)stereoisomers differ. For example, the S isomer is typically 10 timesmore potent than the R isomer at treating cardiovascular conditions. Inaddition, stereo-selective first pass liver metabolism occurs, resultingin higher systemic concentrations (i.e., bioavailability) of the Risomer following oral administration of the racemate. In addition, theinhibitory potency of the isomers against sites on the calcium channeland alpha-1-adrenergic receptors is different (Piascik, Can. J. Physiol.Pharmacol., 68(3):439-446, 1990).

[0011] Verapamil causes several undesirable dose-limiting side effects.These include, inter alia, depression in myocardial activity (Satoh etal., J. Cardio. Pharm., 2:309-318, 1980) and constipation (Hedner etal., Acta Pharmacol. Toxicol., 58(Suppl 2):119-30, 1986; Krevsky et al.,Dig. Dis. Sci., 37(6):919-924, 1992; Thulin, et al., Scand. J. Prim.Health Care Suppl., 1:81-84, 1990). Researchers have attempted toovercome these unwanted side effects by using the individualstereoisomers of verapamil. Harding et al. (U.S. Pat. No. 5,889,060)describe the use of a single stereoisomer, (R)-verapamil, as a treatmentfor angina. Others suggest that (S)-verapamil is more beneficial fortreating angina and atrial fibrillation, while (R)-verapamil is usefulfor reversing multi-drug resistance in cancer chemotherapy (e.g.,McCague et al., U.S. Pat. No. 5,910,601; Harding et al., U.S. Pat. No.5,932,246).

[0012] Longstreth et al. (U.S. Pat. No. 5,955,500) report that the ratioof (R)- and (S)-verapamil may be manipulated to achieve desirablecardiovascular effects while minimizing adverse effects such as slowingof cardiac conduction, alteration in heart rate, and constipation. Sucha strategy has led to the development of a dosage form that releases thestereoisomers of verapamil at different rates in the body for thetreatment of cardiovascular conditions (Gilbert et al., U.S. Pat. No.6,267,980).

[0013] Harding et al. (U.S. Pat. No. 5,932,246) report that the separateadministration of either (R)- or (S)-verapamil reduces the significantconstipative effects caused by racemic verapamil. The patentees suggestthat this therapeutic approach may achieve the desirable cardiovasculareffects of verapamil while reducing the constipation experienced by apatient undergoing treatment.

[0014] In contrast, other researchers have attempted to use theconstipative effects of racemic verapamil as means for treatingintestinal conditions (see, e.g., McCleod, Med. J. Aust., 2(3):119(letter), 1983). Byrne (J. Clin Psy., 48:9, 1987) describes thetreatment of 3 patients diagnosed with irritable bowel syndrome, andreports that 80 mg of racemic verapamil had a constipating effect on thepatients. Similarly, Ahlman et al. (Br. J. Cancer, 54:251-256, 1986)describe the treatment of a patient suffering from midgut carcinoidsyndrome (experiencing severe bouts of diarrhea). According to Ahlman,low doses of racemic verapamil relieved the diarrhea.

[0015] Despite the reported clinical utility of racemic verapamil intreating some intestinal conditions, using the drug in this manner isdangerous because it still exerts its primary effect on thecardiovascular system. Thus, a patient being treated with racemicverapamil for intestinal conditions will likely experience significantunwanted cardiovascular effects from the use of the drug. In addition,while the above-cited reports and others have described racemicverapamil's use in treating some intestinal conditions, none of thesereports has sought to identify, characterize, or use a stereo-isomer ofverapamil to treat intestinal conditions. Given the significanttherapeutic drawbacks noted above, the use of racemic verapamil to treatintestinal conditions is severely limited.

[0016] Mak (U.S. Pat. No. 6,190,691) describes the use of isomers ofverapamil to inhibit TNF production in cells. The reduction of TNFreportedly reduces inflammation. Thus, Mak concludes that the reductionof TNF levels will allow the use of verapamil isomers to treat certainTNF-mediated inflammatory conditions. Mak indicates that theseTNF-mediated inflammatory conditions are selected from inflammatorybowel disease, rheumatoid arthritis, cachexia, asthma, Crohn's disease,endotoxin shock, adult respiratory distress syndrome,ischemic/reperfusion damage, graft-versus-host reactions, boneresorption, transplantation and lupus. Mak, however, does not describethe use of verapamil isomers to treat non-TNF mediated conditions, suchas non-inflammatory conditions of the intestine.

[0017] Thus, there remains a strong need in the art for additionalmethods of treating, preventing, and/or managing intestinal conditionssuch as IBS.

[0018] The present invention is directed to new methods for treating,preventing, and/or managing abnormal increases in gastrointestinalmotility using a stereo-specific form of verapamil. The methods arebased on the unexpected discovery that the R isomer of verapamilexhibits a greater effect on intestinal tissue than on cardiovasculartissue. That is to say, at a given concentration, (R)-verapamil inhibitscontractions in intestinal tissue to a greater extent than incardiovascular tissue. Thus, (R)-verapamil exhibits a relativeintestinal selectivity. In contrast, the more biologically potent Sisomer is approximately equally active in both intestinal andcardiovascular tissue. Accordingly, the R isomer can be used to treat,prevent, and/or manage abnormal increases in gastrointestinal motility,while reducing or exhibiting fewer undesirable cardiovascular effectsassociated with the administration of (S)-verapamil or racemic mixtures.Thus, the present invention overcomes the deficiencies and problems inthe prior art and provides new and effective treatments for abnormalincreases in gastrointestinal motility, and intestinal conditions thatcause the same.

[0019] The methods of the invention involve administering apharmaceutically effective amount of (R)-verapamil, or apharmaceutically acceptable salt thereof, substantially purified fromits S stereoisomer, to a subject in need of such treatment, prevention,and/or management. In one embodiment, the abnormal increases ingastrointestinal motility are due to an increased frequency and/orintensity of intestinal contractions. The present invention may be usedto reduce the frequency and/or intensity of such intestinalcontractions, thereby slowing intestinal motility. The abnormalincreases in gastrointestinal motility may be caused by one or moreintestinal conditions. Thus, the present invention may be used to treat,prevent, and/or manage such intestinal condition(s). Examples ofintestinal conditions that may be treated, prevented, and/or managedaccording to the present invention include, but are not limited to,irritable bowel syndrome (IBS), infectious diseases of the small andlarge intestine, and symptoms of any of the foregoing. Non-inflammatoryconditions, such as IBS, are particularly amenable to the effects of themethods of the present invention. However, those of ordinary skill inthe art are familiar with other types of functional intestinalconditions that produce abnormal increases in gastrointestinal motility,which may also benefit from the present invention.

[0020]FIG. 1 illustrates the relaxation achieved by (R)-verapamil and(S)-verapamil on KCl-induced contractions in rat colon tissue.

[0021]FIG. 2 illustrates the relaxation achieved by (R)-verapamil and(S)-verapamil on KCl-induced contractions in rat aortic tissue.

[0022]FIG. 3 illustrates the effects of (R)-verapamil and (S)-verapamilon KCl-induced contractions in the vas prostatic and vas epididymalportions of rat aortic tissue.

[0023] As used herein, the phrase “modified-release” formulation ordosage form includes a pharmaceutical preparation that achieves adesired release of the drug from the formulation. For example, amodified-release formulation may extend the influence or effect of atherapeutically effective dose of an active compound in a patient. Suchformulations are referred to herein as “extended-release formulations.”In addition to maintaining therapeutic levels of the active compound, amodified-release formulation may also be designed to delay the releaseof the active compound for a specified period. Such compounds arereferred to herein as “delayed onset” formulations or dosage forms.Still further, modified-release formulations may exhibit properties ofboth delayed and extended release formulations, and thus be referred toas “delayed-onset, extended-release” formulations.

[0024] As used herein, the term “pharmaceutically acceptable excipient”includes compounds that are compatible with the other ingredients in apharmaceutical formulation and not injurious to the subject whenadministered in therapeutically effective amounts.

[0025] As used herein, the term “pharmaceutically acceptable salt”includes salts that are physiologically tolerated by a subject. Suchsalts are typically prepared from an inorganic and/or organic acid.Examples of suitable inorganic acids include, but are not limited to,hydrochloric, hydrobromic, hydroiodic, nitric, sulfuric, and phosphoricacid. Organic acids may be aliphatic, aromatic, carboxylic, and/orsulfonic acids. Suitable organic acids include, but are not limited to,formic, acetic, propionic, succinic, camphorsulfonic, citric, fumaric,gluconic, lactic, malic, mucic, tartaric, para-toluenesulfonic,glycolic, glucuronic, maleic, furoic, glutamic, benzoic, anthranilic,salicylic, phenylacetic, mandelic, pamoic, methanesulfonic,ethanesulfonic, pantothenic, benzenesulfonic (besylate), stearic,sulfanilic, alginic, galacturonic, and the like.

[0026] The term “racemic” as used herein means a mixture of the R and Senantiomers of verapamil in which neither enantiomer is substantiallypurified from the other.

[0027] The terms “substantially purified” and “substantially opticallypure,” as used herein to describe (R)-verapamil, refer to a compositioncontaining at least about 60% of the (R)-verapamil stereoisomer byweight, based on the total weight of verapamil. In one embodiment, theamount of optically pure verapamil may be higher, for example, at leastabout 65%, 70%, 75%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%,90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, or 100%, or anyfraction thereof (i.e., 90.1%, 90.2%, etc.), of (R)-verapamil by weight,based on the total weight of verapamil. In a particular embodiment, theamount of optically pure (R)-verapamil may be greater than 99%, 99.1%,99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or may be 100%,by weight, based on the total weight of verapamil. These terms alsodefine the amount of any pharmaceutically acceptable salts of(R)-verapamil.

[0028] The phrase “therapeutically effective amount” of (R)-verapamil,as used herein, refers to the amount of substantially optically pureverapamil (or pharmaceutically acceptable salt thereof), which alone orin combination with other drugs, provides any therapeutic benefit in theprevention, treatment, and/or management of abnormal increases ingastrointestinal motility. Such abnormal increases may be caused by oneor more intestinal conditions, such as irritable bowel syndrome (IBS)and infectious diseases of the small and large intestines. Thus, thesubstantially optically pure verapamil may provide a therapeutic benefitin the prevention, treatment, and/or management of such conditions. Inone embodiment, the therapeutic amount is sufficient to achieve atherapeutic benefit while reducing and/or avoiding at least one unwantedeffect (e.g., unacceptably high levels of cardiovascular activity)typically associated with administration of (S)-verapamil or racemicverapamil. In another embodiment, the therapeutic amount is sufficientto reduce the frequency and/or intensity of intestinal contractions,thereby slowing intestinal motility.

[0029] The present invention is directed to the use of (R)-verapamil, ora pharmaceutically acceptable salt thereof, substantially purified fromits S stereoisomer, for preventing, treating, and/or managing abnormalincreases in gastrointestinal motility. Such abnormal increases may bethe result of one or more intestinal conditions including, but notlimited to, irritable bowel syndrome (IBS), infectious diseases of thesmall or large intestine, and symptoms thereof. Such conditions may becharacterized by complaints of too frequent bowel movements, usuallyincluding symptoms of diarrhea. Other conditions involving abnormallyrapid gastrointestinal motility, abnormal number of bowel movements, anddiarrhea, may also be treated, prevented, and/or managed using thepresently disclosed methods.

[0030] Substantially pure (R)-verapamil may be obtained from a racemicmixture of verapamil, for example, as described in U.S. Pat. Nos.5,892,093 and 5,910,601, the relevant disclosure of each of which isincorporated herein by reference for this purpose. Substantially pure(R)-verapamil may also be obtained from racemic mixtures by HPLCseparation or resolution of the enantiomers using any available means,such as an optically active resolving acid. In addition, (R)-verapamilmay be synthesized by stereospecific synthesis using any appropriatemethodology, examples of which are well known to those of ordinary skillin the art. Chiral synthesis can result in products of high enantiomericpurity. In some cases in which the enantiomeric purity of the product isnot sufficiently high, synthesis methods may be combined with additionalseparation techniques to further enhance the enantiomeric purity of the(R)-verapamil obtained. Processes for resolving racemic verapamil toobtain substantially pure (R)-verapamil are well known to those ofordinary skill in the art.

[0031] The invention also includes pharmaceutical compositions for usein preventing, treating, and/or managing abnormal increases ingastrointestinal motility, and/or the intestinal conditions which causethe same, comprising a therapeutically effective amount of(R)-verapamil, or a pharmaceutically acceptable salt thereof,substantially purified from its S stereoisomer.

[0032] In one embodiment, the substantially pure (R)-verapamil, or apharmaceutically acceptable salt thereof, is provided in apharmaceutical composition for use in treating, preventing, and/ormanaging abnormal increases in gastrointestinal motility and/or theintestinal conditions which cause the same. Such compositions optionallycomprise one or more pharmaceutically acceptable excipients. Suitableexcipients are known to those of skill in the art and described, forexample, in the Handbook of Pharmaceutical Excipients (Kibbe (ed.),3^(rd) Edition (2000), American Pharmaceutical Association, Washington,D.C.), and Remington's Pharmaceutical Sciences (Gennaro (ed.), 20^(th)edition (2000), Mack Publishing, Inc., Easton, Pa.), which, for theirdisclosures relating to excipients and dosage forms, are incorporatedherein by reference. For example, suitable excipients include, but arenot limited to, starches, sugars, microcrystalline cellulose, diluents,granulating agents, lubricants, binders, disintegrating agents, wettingagents, emulsifiers, coloring agents, release agents, coating agents,sweetening agents, flavoring agents, perfuming agents, preservatives,plasticizers, gelling agents, thickeners, hardeners, setting agents,suspending agents, surfactants, humectants, carriers, stabilizers,antioxidants, and combinations thereof.

[0033] The pharmaceutical compositions of the invention are typicallyprovided in dosage forms that are suitable for administration to asubject by a desired route. A number of suitable dosage forms aredescribed below, but are not meant to include all possible choices. Oneof skill in the art is familiar with the various dosage forms that aresuitable for use in the present invention, as described, for example, inRemington's Pharmaceutical Sciences, which has been incorporated byreference above. The most suitable route in any given case will dependon the nature and severity of the gastrointestinal motility and/orintestinal condition being prevented, treated, and/or managed. Forexample, the pharmaceutical compositions may be formulated foradministration orally, nasally, rectally, intravaginally, parenterally,intracisternally, and topically (including buccally and sublingually).

[0034] Formulations suitable for oral administration include, but arenot limited to, capsules, cachets, pills, tablets, lozenges (using aflavored basis, usually sucrose and acacia or tragacanth), powders,granules, solutions, suspensions in an aqueous or non-aqueous liquid,oil-in-water or water-in-oil liquid emulsions, elixirs, syrups,pastilles (using an inert base, such as gelatin and glycerin, or sucroseand acacia), mouth washes, pastes, and the like; each containing apredetermined amount of (R)-verapamil to provide a therapeutic amount ofthe drug in one or more doses.

[0035] In solid dosage forms for oral administration (capsules, tablets,pills, powders, granules and the like), the (R)-verapamil is typicallymixed with one or more pharmaceutically-acceptable excipients, includingcarriers, such as sodium citrate or dicalcium phosphate; fillers orextenders, such as starches, spray-dried or anhydrous lactose, sucrose,glucose, mannitol, dextrose, sorbitol, cellulose (e.g., microcrystallinecellulose; AVICEL™), dihydrated or anhydrous dibasic calcium phosphate,and/or silicic acid; binders, such as acacia, alginic acid,carboxymethylcellulose (sodium), cellulose (microcrystalline), dextrin,ethylcellulose, gelatin, glucose (liquid), guar gum, hydroxypropylcellulose, hydroxypropyl methylcellulose, methylcellulose (e.g.,methylcellulose 2910), polyethylene oxide, povidone, starch(pregelatinized) or syrup; humectants, such as glycerol; disintegratingagents, such as agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, pregelatinised starch, sodium starchglycolate (EXPLOTAB™), crosslinked providone, crosslinked sodiumcarboxymethylcellulose, clays, microcrystalline cellulose (e.g.,AVICEL™), alginates, gums, and/or sodium carbonate; solution retardingagents, such as paraffin; absorption accelerators, such as quaternaryammonium compounds; wetting agents, such as cetyl alcohol or glycerolmonostearate; absorbents, such as kaolin and bentonite clay; lubricants,such as talc, calcium stearate, magnesium stearate, solid polyethyleneglycols, steric acid, sodium stearyl fumarate, magnesium lauryl sulfate,hydrogenated vegetable oil, and/or sodium lauryl sulfate; glidants, suchas calcium silicate, magnesium silicate, colloidal anahydrous silica,and/or talc; flavoring agents, such as synthetic flavor oils andflavoring aromatics, natural oils, extracts from plant leaves, flowers,and fruits, including cinnamon oil, oil of wintergreen, peppermint oils,bay oil, anise oil, eucalyptus, thyme oil, vanilla, citrus oil (e.g.,lemon, orange, grape, lime, and grapefruit), fruit essences (e.g.,apple, banana, pear, peach, strawberry, raspberry, cherry, plum,pineapple, apricot, as so forth); coloring agents and/or pigments, suchas titanium dioxide and/or dyes approved for use in food andpharmaceuticals; buffering agents; dispersing agents; preservatives;and/or diluents. The aforementioned excipients are given as examplesonly and are not meant to include all possible choices.

[0036] Any of these solid dosage forms may optionally be scored orprepared with coatings and shells, such as enteric coatings, andcoatings for modifying the rate of release, examples of which are wellknown in the pharmaceutical-formulating art. For example, such coatingsmay comprise sodium carboxymethylcellulose, cellulose acetate, celluloseacetate phthalate, ethylcellulose, gelatin, pharmaceutical glaze,hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropylmethyl cellulose phthalate, methacrylic acid copolymer, methylcellulose,polyethylene glycol, polyvinyl acetate phthalate, shellac, sucrose,titanium dioxide, wax, or zein. In one embodiment, the coating materialcomprises hydroxypropyl methylcellulose. The coating material mayfurther comprise antiadhesives, such as talc; plasticizers (depending onthe type of coating material selected), such as castor oil, diacetylatedmonoglycerides, dibutyl sebacate, diethyl phthalate, glycerin,polyethylene glycol, propylene glycol, triacetin, triethyl citrate;opacifiers, such as titanium dioxide; and/or coloring agents and/orpigments. The coating process may be carried out by any suitable means,for example, by using a perforated pan system such as the GLATT™,ACCELACOTA™, and/or HICOATER™ apparatuses.

[0037] Tablets may be formed by any suitable process, which are known tothose of ordinary skill in the art. For example, the ingredients may bedry-granulated or wet-granulated by mixing in a suitable apparatusbefore tabletting. Granules of the ingredients to be tabletted may alsobe prepared using suitable spray/fluidization or extrusion/spheronsationtechniques.

[0038] With quick-release tablets, the choice of excipients generallyallows a fast dissolution. The tablets may be conventional instantrelease tablets designed to be taken whole in the typical administrationmanner (i.e., with sufficient amount of water to facilitate swallowing).Alternatively the tablets may be formulated with suitable excipients toact as a fast dissolving and/or fast melting tablet in the oral cavity.Also, the tablet can be in the form of a chewable or effervescent dosageform. With effervescent dosage forms, the tablet is typically added to asuitable liquid that causes it to disintegrate, dissolve, and/ordisperse.

[0039] Tablets typically are designed to have an appropriate hardnessand friability to facilitate manufacture on an industrial scale usingequipment to produce tablets at high speed. Also the tablets are usuallypacked or filled in all kinds of containers. If the tablet has aninsufficient hardness or is friable, the tablet that is taken by thesubject may be broken or crumbled into powder. As a consequence of thisinsufficient hardness or friability, the subject can no longer becertain that the amount of the dose is correct. It should be noted thatthe hardness of tablets, amongst other properties, is influenced by theshape of the tablets. Different shapes of tablets may be used accordingto the present invention. Tablets may be circular, oblate, oblong, orany other shape that is known in the art. The shape of the tablets mayalso influence the disintegration rate.

[0040] Any of the solid compositions may encapsulated in soft and hardgelatin capsules using any of the excipients described above. Forexample, the encapsulated dosage form may include fillers, such aslactose and microcrystalline; glidants, such as colloidal silicondioxide and talc; lubricants, such as magnesium stearate; anddisintegrating agents, such as starch (e.g., maize starch). Usingcapsule filling equipment, the ingredients to be encapsulated are milledtogether, sieved, mixed, packed together, and then delivered into acapsule. The lubricants may be present in an amount from about 0.5%(w/w) to about 2.0% (w/w). In one embodiment, the lubricant is about1.25% (w/w) of the content of the capsule.

[0041] The (R)-verapamil may also be formulated into a liquid dosageform for oral administration. Suitable formulations include emulsions,microemulsions, solutions, suspensions, syrups and elixirs. Theseformulations optionally include diluents commonly used in the art, suchas, for example, water or other solvents, solubilizing agents andemulsifiers, including, but not limited to, ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils, glycerol,tetrahydrofuryl alcohol, polyethylene glycols, fatty acid esters ofsorbitan, and mixtures thereof. In addition, the liquid formulationsoptionally include adjuvants such as wetting agents, emulsifying andsuspending agents, sweetening, flavoring, coloring, perfuming andpreservative agents. Suitable suspension agents include, but are notlimited to, ethoxylated isostearyl alcohols, polyoxyethylene sorbitoland sorbitan esters, microcrystalline cellulose, aluminum metahydroxide,bentonite, agar-agar and tragacanth, xanthan gum,hydroxypropylmethylcellulose, methylcellulose, carageenan, sodiumcarboxymethyl cellulose, and sodium carboxymethylcellulose/microcrystalline cellulose mixtures, sodium carboxymethylcellulose/microcrystalline cellulose mixtures, and/or mixtures thereof.In one embodiment, the suspending agent comprises xanthan gum,carageenan, sodium carboxymethyl cellulose/microcrystalline cellulosemixtures, and/or mixtures thereof. In another embodiment, the suspendingagent is AVICEL™ RC591, AVICEL™ RC581, and/or AVICEL™ CL611 (Avicel is atrademark of FMC Corporation); and/or RC591, RC581 and CL611 (mixturesof microcrystalline cellulose and sodium carboxymethyl cellulose).

[0042] The amount of suspending agent present will vary according to theparticular suspending agent used and the presence or absence of otheringredients which have an ability to act as a suspending agent orcontribute significantly to the viscosity of the composition. Thesuspension may also contain ingredients which improve its taste, forexample sweeteners; bitter-taste maskers, such as sodium chloride;taste-masking flavours, such as contramarum; flavour enhancers, such asmonosodium glutamate; and flavouring agents. Examples of sweetenersinclude bulk sweeteners, such as sucrose, hydrogenated glucose syrup,the sugar alcohols sorbitol and xylitol; and sweetening agents such assodium cyclamate, sodium saccharin, aspartame, and ammoniumglycyrrhizinate. The liquid formulations may further comprise one ormore buffering agents, as needed, to maintain the desired pH.

[0043] The liquid formulations of the present invention may also befilled into soft gelatin capsules. For example, the liquid may include asolution, suspension, emulsion, microemulsion, precipitate, or any otherdesired liquid media carrying the (R)-verapamil. The liquid may bedesigned to improve the solubility of the (R)-verapamil upon release, ormay be designed to form a drug-containing emulsion or dispersed phaseupon release. Examples of such techniques are well known in the art.Soft gelatin capsules may be coated, as desired, with a functionalcoating, as described below, to delay the release of the drug.

[0044] For rectal or vaginal administration, the composition may beprovided as a suppository. Suppositories optionally comprise one or morenon-irritating excipients, for example, polyethylene glycol, asuppository wax, or a salicylate. Such excipients may be selected on thebasis of desirable physical properties. For example, a compound that issolid at room temperature but liquid at body temperature will melt inthe rectum or vaginal cavity and release the active compound. Theformulation may alternatively be provided as an enema for rectaldelivery. Formulations suitable for vaginal administration also includepessaries, tampons, creams, gels, pastes, foams or spray formulationscontaining such carriers, examples of which are known in the art.

[0045] Formulations suitable for topical or transdermal administrationinclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants. Such formulations optionally containexcipients such as animal and vegetable fats, oils, waxes, paraffins,starch, tragacanth, cellulose derivatives, polyethylene glycols,silicones, bentonites, silicic acid, talc, zinc oxide, or mixturesthereof. Powders and sprays may also contain excipients such as lactose,talc, silicic acid, aluminum hydroxide, calcium silicates and polyamidepowder. Additionally, sprays may contain propellants, such aschlorofluoro-hydrocarbons and volatile unsubstituted hydrocarbons, suchas butane and propane.

[0046] Transdermal patches have the added advantage of providingcontrolled delivery of the mixture of the invention to the body. Suchdosage forms can be made by dissolving, dispersing or otherwiseincorporating a pharmaceutical composition containing (R)-verapamil in asuitable medium, such as an elastomeric matrix material. Absorptionenhancers can also be used to increase the flux of the mixture acrossthe skin. The rate of such flux can be controlled by either providing arate-controlling membrane or dispersing the compound in a polymer matrixor gel.

[0047] For parenteral administration, such as administration byinjection (including, but not limited to, subcutaneous, bolus injection,intramuscular, intraperitoneal, and intravenous), the pharmaceuticalcompositions may be formulated as isotonic suspensions, solutions oremulsions in oily or aqueous vehicles, and may contain formulatoryagents such as suspending, stabilizing, or dispersing agents.Alternatively, the compositions may be provided in dry form such as apowder, crystalline or freeze-dried solid for reconstitution withsterile pyrogen-free water or isotonic saline before use. They may bepresented, for example, in sterile ampoules or vials.

[0048] Examples of suitable aqueous and nonaqueous excipients includewater, ethanol, polyols (such as glycerol, propylene glycol,polyethylene glycol, and the like), oils, injectable organic esters, andmixtures thereof. Proper fluidity can be maintained, for example, by theuse of coating materials and surfactants.

[0049] These compositions may also contain adjuvants such aspreservatives, wetting agents, emulsifying agents and dispersing agents.Prevention of the action of microorganisms may be acheived by theinclusion of various antibacterial and/or antifungal agents, forexample, paraben, chlorobutanol, phenol sorbic acid, and the like. Itmay also be desirable to include isotonic agents, such as sugars, sodiumchloride, and the like in the compositions. In addition, prolongedabsorption of the injectable pharmaceutical form may be brought about bythe inclusion of agents which delay absorption such as aluminummonostearate and gelatin.

[0050] In order to prolong the therapeutic effect of a drug, it is oftendesirable to slow the absorption of the drug from a subcutaneous orintramuscular injection. This may be accomplished by the use of a liquidsuspension of crystalline or amorphous material having low solubility.The rate of absorption of the drug then depends upon its rate ofdissolution which, in turn, may depend upon crystal size and crystallineform. Alternatively, delayed absorption of a parenterally-administeredform can be accomplished by dissolving or suspending the drug in an oilvehicle.

[0051] In addition to the common dosages forms described above, thecompositions of the present invention may be formulated into a dosageform that modifies the release of (R)-verapamil. Examples of suitablemodified release formulations, which may be used in accordance with thepresent invention include, but are not limited to, matrix systems,osmotic pumps, and membrane controlled dosage forms. These formulationstypically comprise (R)-verapamil and/or one or more pharmaceuticallyacceptable salts thereof. Suitable pharmaceutically acceptable salts arediscussed above.

[0052] Different types of modified dosage forms are briefly describedbelow. A more detailed discussion of such forms may also be found in,for example The Handbook of Pharmaceutical Controlled ReleaseTechnology, D. L. Wise (ed.), Marcel Dekker, Inc., New York (2000); andalso in Treatise on Controlled Drug Delivery: Fundamentals,Optimization, and Applications, A. Kydonieus (ed.), Marcel Dekker, Inc.,New York, (1992), the relevant contents of each of which is herebyincorporated by reference for this purpose. Examples of modified releasedosage forms are also described, for example, in U.S. Pat. Nos.3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533;5,059,595; 5,591,767; 5,120,548; 5,073,543; 5,639,476; 5,354,556; and5,733,566, the disclosures of which, for their discussions ofpharmaceutical formulations, are incorporated herein by reference.

[0053] Advantages of modified-release formulations may include extendedactivity of the drug, reduced dosage frequency, increased patientcompliance, and the ability to deliver the drug to specific sites in theintestinal tract. Suitable components (e.g., polymers, excipients, etc.)for use in modified-release formulations, and methods of producing thesame, are also described, e.g., in U.S. Pat. No. 4,863,742, which isincorporated by reference for these purposes.

[0054] Matrix-Based Dosage Forms

[0055] In some embodiments, the modified release formulations of thepresent invention are provided as matrix-based dosage forms. Matrixformulations according to the invention may include hydrophilic, e.g.,water-soluble, and/or hydrophobic, e.g., water-insoluble, polymers. Thematrix formulations of the present invention may optionally be preparedwith functional coatings, which may be enteric, e.g., exhibiting apH-dependent solubility, or non-enteric, e.g., exhibiting apH-independent solubility.

[0056] Matrix formulations of the present invention may be prepared byusing, for example, direct compression or wet granulation. A functionalcoating, as noted above, may then be applied in accordance with theinvention. Additionally, a barrier or sealant coat may be applied over amatrix tablet core prior to application of a functional coating. Thebarrier or sealant coat may serve the purpose of separating an activeingredient from a functional coating, which may interact with the activeingredient, or it may prevent moisture from contacting the activeingredient. Details of barriers and sealants are provided below.

[0057] In a matrix-based dosage form in accordance with the presentinvention, the (R)-verapamil and optional pharmaceutically acceptableexcipient(s) are dispersed within a polymeric matrix, which typicallycomprises one or more water-soluble polymers and/or one or morewater-insoluble polymers. The drug may be released from the dosage formby diffusion and/or erosion. Such matrix systems are described in detailby Wise and Kydonieus, supra.

[0058] Suitable water-soluble polymers include, but are not limited to,polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose,hydroxypropylcellulose, hydroxypropylmethyl cellulose or polyethyleneglycol, and/or mixtures thereof.

[0059] Suitable water-insoluble polymers include, but are not limitedto, ethylcellulose, cellulose acetate cellulose propionate, celluloseacetate propionate, cellulose acetate butyrate, cellulose acetatephthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethylmethacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate),and poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecylacrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene)high density, poly(ethylene oxide), poly(ethylene terephthalate),poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) orpolyurethane, and/or mixtures thereof.

[0060] Suitable pharmaceutically acceptable excipients include, but arenot limited to, carriers, such as sodium citrate and dicalciumphosphate; fillers or extenders, such as stearates, silicas, gypsum,starches, lactose, sucrose, glucose, mannitol, talc, and silicic acid;binders, such as hydroxypropyl methylcellulose, hydroxymethyl-cellulose,alginates, gelatin, polyvinyl pyrrolidone, sucrose and acacia;humectants, such as glycerol; disintegrating agents, such as agar,calcium carbonate, potato and tapioca starch, alginic acid, certainsilicates, EXPLOTAB™, crospovidone, and sodium carbonate; solutionretarding agents, such as paraffin; absorption accelerators, such asquaternary ammonium compounds; wetting agents, such as cetyl alcohol andglycerol monostearate; absorbents, such as kaolin and bentonite clay;lubricants, such as talc, calcium stearate, magnesium stearate, solidpolyethylene glycols, and sodium lauryl sulfate; stabilizers, such asfumaric acid; coloring agents; buffering agents; dispersing agents;preservatives; organic acids; and organic bases. The aforementionedexcipients are given as examples only and are not meant to include allpossible choices. Additionally, many excipients may have more than onerole or function, or be classified in more than one group; theclassifications are descriptive only, and not intended to limit any useof a particular excipient.

[0061] In one embodiment, a matrix-based dosage form comprises(R)-verapamil; a filler, such as starch, lactose, or microcrystallinecellulose (AVICEL™); a binder/controlled-release polymer, such ashydroxypropyl methylcellulose or polyvinyl pyrrolidone; a disintegrant,such as, EXPLOTAB™, crospovidone, or starch; a lubricant, such asmagnesium stearate or stearic acid; a surfactant, such as sodium laurylsulfate or polysorbates; and a glidant, such as colloidal silicondioxide (AEROSIL™) or talc.

[0062] The amounts and types of polymers, and the ratio of water-solublepolymers to water-insoluble polymers in the inventive formulations aregenerally selected to achieve a desired release profile of(R)-verapamil. For example, by increasing the amount ofwater-insoluble-polymer relative to the amount of water-soluble polymer,the release of the drug may be delayed or slowed. This is due, in part,to an increased impermeability of the polymeric matrix, and, in somecases, to a decreased rate of erosion during transit through the GItract.

[0063] Osmotic Pump Dosage Forms

[0064] In another embodiment, the modified release formulations of thepresent invention are provided as osmotic pump dosage forms. In anosmotic pump dosage form, a core containing the (R)-verapamil andoptionally one or more osmotic excipients is typically encased by asemipermeable membrane having at least one orifice. The semipermeablemembrane is generally permeable to water, but impermeable to the drug.When the system is exposed to body fluids, water penetrates through thesemipermeable membrane into the core containing the drug and optionalosmotic excipients. The osmotic pressure increases within the dosageform. Consequently, the drug is released through the orifice(s) in anattempt to equalize the osmotic pressure across the semipermeablemembrane.

[0065] In more complex pumps, the dosage form may contain two internalcompartments in the core. The first compartment contains the drug andthe second compartment may contain a polymer, which swells on contactwith aqueous fluid. After ingestion, this polymer swells into thedrug-containing compartment, diminishing the volume occupied by thedrug, thereby delivering the drug from the device at a controlled rateover an extended period of time. Such dosage forms are often used when azero order release profile is desired.

[0066] Osmotic pumps are well known in the art. For example, U.S. Pat.Nos. 4,088,864, 4,200,098, and 5,573,776, each of which is herebyincorporated by reference for this purpose, describe osmotic pumps andmethods of their manufacture. The osmotic pumps useful in accordancewith the present invention may be formed by compressing a tablet of anosmotically active drug, or an osmotically inactive drug in combinationwith an osmotically active agent, and then coating the tablet with asemipermeable membrane which is permeable to an exterior aqueous-basedfluid but impermeable to the drug and/or osmotic agent.

[0067] One or more delivery orifices may be drilled through thesemipermeable membrane wall. Alternatively, one or more orifices in thewall may be formed by incorporating leachable pore-forming materials inthe wall. In operation, the exterior aqueous-based fluid is imbibedthrough the semipermeable membrane wall and contacts the drug to form asolution or suspension of the drug. The drug solution or suspension isthen pumped out through the orifice as fresh fluid is imbibed throughthe semipermeable membrane.

[0068] Typical materials for the semipermeable membrane includesemipermeable polymers known in the art to be useful in osmosis andreverse osmosis membranes, such as cellulose acylate, cellulosediacylate, cellulose triacylate, cellulose acetate, cellulose diacetate,cellulose triacetate, agar acetate, amylose triacetate, beta glucanacetate, acetaldehyde dimethyl acetate, cellulose acetate ethylcarbamate, polyamides, polyurethanes, sulfonated polystyrenes, celluloseacetate phthalate, cellulose acetate methyl carbamate, cellulose acetatesuccinate, cellulose acetate dimethyl aminoacetate, cellulose acetateethyl carbamate, cellulose acetate chloracetate, cellulose dipalmitate,cellulose dioctanoate, cellulose dicaprylate, cellulose dipentanlate,cellulose acetate valerate, cellulose acetate succinate, cellulosepropionate succinate, methyl cellulose, cellulose acetate p-toluenesulfonate, cellulose acetate butyrate, lightly cross-linked polystyrenederivatives, cross-linked poly(sodium styrene sulfonate),poly(vinylbenzyltrimethyl ammonium chloride), cellulose acetate,cellulose diacetate, cellulose triacetate, and/or mixtures thereof.

[0069] The osmotic agents that can be used in the pump are typicallysoluble in the fluid that enters the device following administration,resulting in an osmotic pressure gradient across the semipermeable wallagainst the exterior fluid. Suitable osmotic agents include, but are notlimited to, magnesium sulfate, calcium sulfate, magnesium chloride,sodium chloride, lithium chloride, potassium sulfate, sodium carbonate,sodium sulfite, lithium sulfate, potassium chloride, sodium sulfate,d-mannitol, urea, sorbitol, inositol, raffinose, sucrose, glucose,hydrophilic polymers such as cellulose polymers, and/or mixturesthereof.

[0070] As discussed above, the osmotic pump dosage form may contain asecond compartment containing a swellable polymer. Suitable swellablepolymers typically interact with water and/or aqueous biological fluids,which causes them to swell or expand to an equilibrium state. Acceptablepolymers exhibit the ability to swell in water and/or aqueous biologicalfluids, retaining a significant portion of such imbibed fluids withintheir polymeric structure, so as into increase the hydrostatic pressurewithin the dosage form. The polymers may swell or expand to a very highdegree, usually exhibiting a 2- to 50-fold volume increase. The polymerscan be non-cross-linked or cross-linked. In one embodiment, theswellable polymers are hydrophilic polymers. Suitable polymers include,but are not limited to, poly(hydroxy alkyl methacrylate) having amolecular weight of from 30,000 to 5,000,000; kappa-carrageenan;polyvinylpyrrolidone having a molecular weight of from 10,000 to360,000; anionic and cationic hydrogels; polyelectrolyte complexes;poly(vinyl alcohol) having low amounts of acetate, cross-linked withglyoxal, formaldehyde, or glutaraldehyde, and having a degree ofpolymerization from 200 to 30,000; a mixture including methyl cellulose,cross-linked agar and carboxymethyl cellulose; a water-insoluble,water-swellable copolymer produced by forming a dispersion of finelydivided maleic anhydride with styrene, ethylene, propylene, butylene orisobutylene; water-swellable polymers of N-vinyl lactams; and/ormixtures of any of the foregoing.

[0071] The term “orifice” as used herein comprises means and methodssuitable for releasing the drug from the dosage form. The expressionincludes one or more apertures or orifices that have been bored throughthe semipermeable membrane by mechanical procedures. Alternatively, anorifice may be formed by incorporating an erodible element, such as agelatin plug, in the semipermeable membrane. In such cases, the pores ofthe semipermeable membrane form a “passageway” for the passage of thedrug. Such “passageway” formulations are described, for example, in U.S.Pat. No. Nos. 3,845,770 and 3,916,899, the relevant disclosures of whichare incorporated herein by reference for this purpose.

[0072] The osmotic pumps useful in accordance with this invention may bemanufactured by techniques known in the art. For example, the drug andother ingredients may be milled together and pressed into a solid havingthe desired dimensions (e.g., corresponding to the first compartment).The swellable polymer is then formed, placed in contact with the drug,and both are surrounded with the semipermeable agent. If desired, thedrug component and polymer component may be pressed together beforeapplying the semipermeable membrane. The semipermeable membrane may beapplied by any suitable method, for example, by molding, spraying, ordipping.

[0073] Membrane-Controlled Dosage Forms

[0074] The modified release formulations of the present invention mayalso be provided as membrane controlled formulations. Membranecontrolled formulations of the present invention can be made bypreparing a rapid release core, which may be a monolithic (e.g., tablet)or multi-unit (e.g., pellet) type, and coating the core with a membrane.The membrane-controlled core can then be further coated with afunctional coating. In between the membrane-controlled core andfunctional coating, a barrier or sealant may be applied. Details ofmembrane-controlled dosage forms are provided below.

[0075] In one embodiment, the (R)-verapamil may be provided in amultiparticulate membrane controlled formulation. The (R)-verapamil maybe formed into an active core by applying the drug to a nonpareil seedhaving an average diameter in the range of about 0.4 to about 1.1 mm orabout 0.85 to about 1.00 mm. The (R)-verapamil may be applied with orwithout additional excipients onto the inert cores, and may be sprayedfrom solution or suspension using a fluidized bed coater (e.g., Wurstercoating) or pan coating system. Alternatively, the (R)-verapamil may beapplied as a powder onto the inert cores using a binder to bind the(R)-verapamil onto the cores. Active cores may also be formed byextrusion of the core with suitable plasticizers (described below) andany other processing aids as necessary.

[0076] The modified release formulations of the present inventioncomprise at least one polymeric material, which is applied as a membranecoating to the drug-containing cores. Suitable water-soluble polymersinclude, but are not limited to, polyvinyl alcohol,polyvinylpyrrolidone, methylcellulose, hydroxypropylcellulose,hydroxypropylmethyl cellulose or polyethylene glycol, and/or mixturesthereof.

[0077] Suitable water-insoluble polymers include, but are not limitedto, ethylcellulose, cellulose acetate cellulose propionate, celluloseacetate propionate, cellulose acetate butyrate, cellulose acetatephthalate, cellulose triacetate, poly(methyl methacrylate), poly(ethylmethacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate),and poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(laurylmethacrylate), poly(phenyl methacrylate), poly(methyl acrylate),poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecylacrylate), poly(ethylene), poly(ethylene) low density, poly(ethylene)high density, poly(ethylene oxide), poly(ethylene terephthalate),poly(vinyl isobutyl ether), poly(vinyl acetate), poly(vinyl chloride) orpolyurethane, and/or mixtures thereof.

[0078] EUDRAGIT™ polymers (available from Rohm Pharma) are polymericlacquer substances based on acrylates and/or methacrylates. A suitablepolymer that is freely permeable to the active ingredient and water isEUDRAGIT™ RL. A suitable polymer that is slightly permeable to theactive ingredient and water is EUDRAGIT™ RS. Other suitable polymerswhich are slightly permeable to the active ingredient and water, andexhibit a pH-dependent permeability include, but are not limited to,EUDRAGIT™ L, EUDRAGIT™ S, and EUDRAGIT™ E.

[0079] EUDRAGIT™ RL and RS are acrylic resins comprising copolymers ofacrylic and methacrylic acid esters with a low content of quaternaryammonium groups. The ammonium groups are present as salts and give riseto the permeability of the lacquer films. EUDRAGIT™ RL and RS are freelypermeable (RL) and slightly permeable (RS), respectively, independent ofpH. The polymers swell in water and digestive juices, in apH-independent manner. In the swollen state, they are permeable to waterand to dissolved active compounds.

[0080] EUDRAGIT™ L is an anionic polymer synthesized from methacrylicacid and methacrylic acid methyl ester. It is insoluble in acids andpure water. It becomes soluble in neutral to weakly alkaline conditions.The permeability of EUDRAGIT™ L is pH dependent. Above pH 5.0, thepolymer becomes increasingly permeable.

[0081] In one embodiment comprising a membrane-controlled dosage form,the polymeric material comprises methacrylic acid co-polymers, ammoniomethacrylate co-polymers, or a mixture thereof. Methacrylic acidco-polymers such as EUDRAGIT™ S and EUDRAGIT™ L (Rohm Pharma) areparticularly suitable for use in the controlled release formulations ofthe present invention. These polymers are gastroresistant andenterosoluble polymers. Their polymer films are insoluble in pure waterand diluted acids. They dissolve at higher pHs, depending on theircontent of carboxylic acid. EUDRAGIT™ S and EUDRAGIT™ L can be used assingle components in the polymer coating or in combination in any ratio.By using a combination of the polymers, the polymeric material mayexhibit a solubility at a pH between the pHs at which EUDRAGIT™ L andEUDRAGIT™ S are separately soluble.

[0082] The membrane coating may comprise a polymeric material comprisinga major proportion (i.e., greater than 50% of the total polymericcontent) of one or more pharmaceutically acceptable water-solublepolymers, and optionally a minor proportion (i.e., less than 50% of thetotal polymeric content) of one or more pharmaceutically acceptablewater-insoluble polymers. Alternatively, the membrane coating maycomprise a polymeric material comprising a major proportion (i.e.,greater than 50% of the total polymeric content) of one or morepharmaceutically acceptable water-insoluble polymers, and optionally aminor proportion (i.e., less than 50% of the total polymeric content) ofone or more pharmaceutically acceptable water-soluble polymers.

[0083] Ammonio methacrylate co-polymers such as Eudragit RS and EudragitRL (Rohm Pharma) are suitable for use in the controlled releaseformulations of the present invention. These polymers are insoluble inpure water, dilute acids, buffer solutions, or digestive fluids over theentire physiological pH range. The polymers swell in water and digestivefluids independently of pH. In the swollen state they are then permeableto water and dissolved actives. The permeability of the polymers dependson the ratio of ethylacrylate (EA), methyl methacrylate (MMA), andtrimethylammonioethyl methacrylate chloride (TAMCl) groups in thepolymer. Those polymers having EA:MMA:TAMCl ratios of 1:2:0.2 (EudragitRL) are more permeable than those with ratios of 1:2:0.1 (Eudragit RS).Polymers of Eudragit RL are insoluble polymers of high permeability.Polymers of Eudragit RS are insoluble films of low permeability.

[0084] The ammonio methacrylate co-polymers may be combined in anydesired ratio. For example, a ratio of Eudragit RS:Eudragit RL (90:10)may be used. The ratios may furthermore be adjusted to provide a delayin release of the drug. For example, the ratio of Eudragit RS:EudragitRL may be about 100:0 to about 80:20, about 100:0 to about 90:10, or anyratio in between. In such formulations, the less permeable polymerEudragit RS would generally comprise the majority of the polymericmaterial.

[0085] The ammonio methacrylate co-polymers may be combined with themethacrylic acid co-polymers within the polymeric material in order toachieve the desired delay in release of the drug. Ratios of ammoniomethacrylate co-polymer (e.g., Eudragit RS) to methacrylic acidco-polymer in the range of about 99:1 to about 20:80 may be used. Thetwo types of polymers can also be combined into the same polymericmaterial, or provided as separate coats that are applied to the core.

[0086] In addition to the Eudragit polymers described above, a number ofother such copolymers may be used to control drug release. These includemethacrylate ester co-polymers (e.g., Eudragit NE 30D). Furtherinformation on the Eudragit polymers can be found in “Chemistry andApplication Properties of Polymethacrylate Coating Systems,” in AqueousPolymeric Coatings for Pharmaceutical Dosage Forms, ed. James McGinity,Marcel Dekker Inc., New York, pg 109-114).

[0087] The coating membrane may further comprise one or more solubleexcipients so as to increase the permeability of the polymeric material.Suitably, the soluble excipient is selected from among a solublepolymer, a surfactant, an alkali metal salt, an organic acid, a sugar,and a sugar alcohol. Such soluble excipients include, but are notlimited to, polyvinyl pyrrolidone, polyethylene glycol, sodium chloride,surfactants such as sodium lauryl sulfate and polysorbates, organicacids such as acetic acid, adipic acid, citric acid, fumaric acid,glutaric acid, malic acid, succinic acid, and tartaric acid, sugars suchas dextrose, fructose, glucose, lactose and sucrose, sugar alcohols suchas lactitol, maltitol, mannitol, sorbitol and xylitol, xanthan gum,dextrins, and maltodextrins. In some embodiments, polyvinyl pyrrolidone,mannitol, and/or polyethylene glycol can be used as soluble excipients.The soluble excipient(s) may be used in an amount of from about 1% toabout 10% by weight, based on the total dry weight of the polymer.

[0088] In another embodiment, the polymeric material comprises one ormore water-insoluble polymers, which are also insoluble ingastrointestinal fluids, and one or more water-soluble pore-formingcompounds. For example, the water-insoluble polymer may comprise aterpolymer of polyvinylchloride, polyvinylacetate, and/orpolyvinylalcohol. Suitable water-soluble pore-forming compounds include,but are not limited to, saccharose, sodium chloride, potassium chloride,polyvinylpyrrolidone, and/or polyethyleneglycol. The pore-formingcompounds may be uniformly or randomly distributed throughout thewater-insoluble polymer. Typically, the pore-forming compounds compriseabout 1 part to about 35 parts for each about 1 to about 10 parts of thewater-insoluble polymers.

[0089] When such dosage forms come in to contact with the dissolutionmedia (e.g., intestinal fluids), the pore-forming compounds within thepolymeric material dissolve to produce a porous structure through whichthe drug diffuses. Such formulations are described in more detail inU.S. Pat. No. 4,557,925, which relevant part is incorporated herein byreference for this purpose. The porous membrane may also be coated withan enteric coating, as described herein, to inhibit release in thestomach.

[0090] In one embodiment, such pore forming controlled release dosageforms comprise (R)-verapamil; a filler, such as starch, lactose, ormicrocrystalline cellulose (AVICEL™); a binder/controlled releasepolymer, such as hydroxypropyl methylcellulose or polyvinyl pyrrolidone;a disintegrant, such as, EXPLOTAB™, crospovidone, or starch; alubricant, such as magnesium stearate or stearic acid; a surfactant,such as sodium lauryl sulphate or polysorbates; and a glidant, such ascolloidal silicon dioxide (AEROSIL™) or talc.

[0091] The polymeric material may also include one or more auxiliaryagents such as fillers, plasticizers, and/or anti-foaming agents.Representative fillers include talc, fumed silica, glycerylmonostearate, magnesium stearate, calcium stearate, kaolin, colloidalsilica, gypsum, micronized silica, and magnesium trisilicate. Thequantity of filler used typically ranges from about 2% to about 300% byweight, and can range from about 20 to about 100%, based on the totaldry weight of the polymer. In one embodiment, talc is the filler.

[0092] The coating membranes, and functional coatings as well, can alsoinclude a material that improves the processing of the polymers. Suchmaterials are generally referred to as plasticizers and include, forexample, adipates, azelates, benzoates, citrates, isoebucates,phthalates, sebacates, stearates and glycols. Representativeplasticizers include acetylated monoglycerides, butyl phthalyl butylglycolate, dibutyl tartrate, diethyl phthalate, dimethyl phthalate,ethyl phthalyl ethyl glycolate, glycerin, ethylene glycol, propyleneglycol, triacetin citrate, triacetin, tripropinoin, diacetin, dibutylphthalate, acetyl monoglyceride, polyethylene glycols, castor oil,triethyl citrate, polyhydric alcohols, acetate esters, gylceroltriacetate, acetyl triethyl citrate, dibenzyl phthalate, dihexylphthalate, butyl octyl phthalate, diisononyl phthalate, butyl octylphthalate, dioctyl azelate, epoxidised tallate, triisoctyl trimellitate,diethylhexyl phthalate, di-n-octyl phthalate, di-i-octyl phthalate,di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl phthalate,tri-2-ethylhexyl trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexylsebacate, di-2-ethylhexyl azelate, dibutyl sebacate, glycerylmonocaprylate, and glyceryl monocaprate. In one embodiment, theplasticizer is dibutyl sebacate. The amount of plasticizer used in thepolymeric material typically ranges from about 10% to about 50%, forexample, about 10, 20, 30, 40, or 50%, based on the weight of the drypolymer.

[0093] Anti-foaming agents can also be included. In one embodiment, theanti-foaming agent is simethicone. The amount of anti-foaming agent usedtypically comprises from about 0% to about 0.5% of the finalformulation.

[0094] The amount of polymer to be used in the membrane controlledformulations is typically adjusted to achieve the desired drug deliveryproperties, including the amount of drug to be delivered, the rate andlocation of drug delivery, the time delay of drug release, and the sizeof the multiparticulates in the formulation. The amount of polymerapplied typically provides an about 10 to about 100% weight gain to thecores. In one embodiment, the weight gain from the polymeric materialranges from about 25 to about 70%.

[0095] The combination of all solid components of the polymericmaterial, including co-polymers, fillers, plasticizers, and optionalexcipients and processing aids, typically provides an about 10 to about450% weight gain on the cores. In one embodiment, the weight gain isabout 30 to about 160%.

[0096] The polymeric material can be applied by any known method, forexample, by spraying using a fluidized bed coater (e.g., Wurstercoating) or pan coating system. Coated cores are typically dried orcured after application of the polymeric material. Curing means that themultiparticulates are held at a controlled temperature for a timesufficient to provide stable release rates. Curing can be performed, forexample, in an oven or in a fluid bed drier. Curing can be carried outat any temperature above room temperature.

[0097] A sealant or barrier can also be applied to the polymericcoating. A sealant or barrier layer may also be applied to the coreprior to applying the polymeric material. A sealant or barrier layer isnot intended to modify the release of (R)-verapamil. Suitable sealantsor barriers are permeable or soluble agents such as hydroxypropylmethylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose,and xanthan gum.

[0098] Other agents can be added to improve the processability of thesealant or barrier layer. Such agents include talc, colloidal silica,polyvinyl alcohol, titanium dioxide, micronized silica, fumed silica,glycerol monostearate, magnesium trisilicate and magnesium stearate, ora mixture thereof. The sealant or barrier layer can be applied fromsolution (e.g., aqueous) or suspension using any known means, such as afluidized bed coater (e.g., Wurster coating) or pan coating system.Suitable sealants or barriers include, for example, OPADRY WHITEY-1-7000 and OPADRY OY/B/28920 WHITE, each of which is available fromColorcon Limited, England.

[0099] The invention also provides an oral dosage form containing amultiparticulate (R)-verapamil formulation as hereinabove defined, inthe form of caplets, capsules, particles for suspension prior to dosing,sachets, or tablets. When the dosage form is in the form of tablets, thetablets may be disintegrating tablets, fast dissolving tablets,effervescent tablets, fast melt tablets, and/or mini-tablets. The dosageform can be of any shape suitable for oral administration of a drug,such as spheroidal, cube-shaped oval, or ellipsoidal. The dosage formscan be prepared from the multiparticulates in a manner known in the artand include additional pharmaceutically acceptable excipients, asdesired.

[0100] All of the particular embodiments described above, including butnot limited to, matrix-based, osmotic pump-based, soft gelatin capsules,and/or membrane-controlled forms, which may further take the form ofmonolithic and/or multi-unit dosage forms, may have a functionalcoating. Such coatings generally serve the purpose of delaying therelease of the drug for a predetermined period. For example, suchcoatings may allow the dosage form to pass through the stomach withoutbeing subjected to stomach acid or digestive juices. Thus, such coatingsmay dissolve or erode upon reaching a desired point in thegastrointestinal tract, such as the upper intestine.

[0101] Such functional coatings may exhibit pH-dependent orpH-independent solubility profiles. Those with pH-independent profilesgenerally erode or dissolve away after a predetermined period, and theperiod is generally directly proportional to the thickness of thecoating. Those with pH-dependent profiles, on the other hand, maymaintain their integrity while in the acid pH of the stomach, butquickly erode or dissolve upon entering the more basic upper intestine.

[0102] Thus, a matrix-based, osmotic pump-based, or membrane-controlledformulation may be further coated with a functional coating that delaysthe release of the drug. For example, a membrane-controlled formulationmay be coated with an enteric coating that delays the exposure of themembrane-controlled formulation until the upper intestine is reached.Upon leaving the acidic stomach and entering the more basic intestine,the enteric coating dissolves. The membrane-controlled formulation thenis exposed to gastrointestinal fluid, and then releases the(R)-verapamil over an extended period, in accordance with the invention.Examples of functional coatings such as these are well known to those inthe art.

[0103] Any of the oral dosage forms described herein may be provided inthe form of caplets, capsules, beads, granules, particles for suspensionprior to dosing, sachets, or tablets. When the dosage form is in theform of tablets, the tablets may be disintegrating tablets, fastdissolving tablets, effervescent tablets, fast melt tablets, and/ormini-tablets. The dosage form can be of any shape suitable for oraladministration of a drug, such as spheroidal, cube-shaped oval, orellipsoidal.

[0104] The thickness of the polymer in the formulations, the amounts andtypes of polymers, and the ratio of water-soluble polymers towater-insoluble polymers in the modified-release formulations aregenerally selected to achieve a desired release profile of(R)-verapamil. For example, by increasing the amount ofwater-insoluble-polymer relative to the water-soluble polymer, therelease of the drug may be delayed or slowed.

[0105] The amount of the dose administered, as well as the dosefrequency, will vary depending on the particular dosage form used androute of administration. The amount and frequency of administration willalso vary according to the age, body weight, and response of theindividual subject. Typical dosing regimens can readily be determined bya competent physician without undue experimentation. It is also notedthat the clinician or treating physician will know how and when tointerrupt, adjust, or terminate therapy in conjunction with individualsubject response.

[0106] In general, the total daily dosage for treating, preventing,and/or managing the abnormal increases in gastrointestinal motilityand/or the intestinal conditions that cause the same with any of theformulations according to the present invention is from about 1 mg toabout 1000 mg, or about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55,60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 250, 300, 350, 400,450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, or 1000 mg, orany number in between, of substantially pure (R)-verapamil, or apharmaceutically acceptable salt thereof. For example, for an orallyadministered dosage form, the total daily dose may range from about 30mg to about 600 mg, or from about 60 mg to about 480 mg, or from about120 mg to about 480 mg, or from about 120 mg to about 240 mg.Accordingly, a single oral dose may be formulated to contain about 1, 5,10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 70, 80, 90, 100, 120, 140,150, 160, 180, 200, 220, 240, 250, 260, 280, 300, 320, 340, 350, 360,380, 400, 420, 440, 450, 460, 480, 500, 520, 540, 550, 560, 580, or 600mg, or any number in between, of substantially pure (R)-verapamil. Thepharmaceutical compositions containing (R)-verapamil may be administeredin single or divided doses 1, 2, 3, 4, or more times each day.Alternatively, the dose may be delivered once every 2, 3, 4, 5, or moredays. In one embodiment, the pharmaceutical compositions areadministered once per day.

[0107] Any of the pharmaceutical compositions and dosage forms describedherein may further comprise one or more pharmaceutically activecompounds other than (R)-verapamil. Such compounds may be included totreat, prevent, and/or manage the same condition being treated,prevented, and/or managed with (R)-verapamil, or a different one. Thoseof skill in the art are familiar with examples of the techniques forincorporating additional active ingredients into compositions comprising(R)-verapamil. Alternatively, such additional pharmaceutical compoundsmay be provided in a separate formulation and co-administered to asubject with an (R)-verapamil composition according to the presentinvention. Such separate formulations may be administered before, after,or simultaneously with the administration of the (R)-verapamilcompositions of the present invention.

[0108] The invention is further illustrated by reference to thefollowing examples. It will be apparent to those skilled in the art thatmany modifications, both to the materials and methods, may be practicedwithout departing from the purpose and scope of the invention.

EXAMPLES Example 1 Activity of (R)-Verapamil and (S)-Verapamil in theColon

[0109] (S)-Verapamil and (R)-Verapamil were obtained from Aonima MaterieSintetiche E Affini S.P.A. (Milan, Italy). Rat colon tissue was preparedand mounted in a tissue bath by standard methods familiar to thoseskilled in the art. The physiological medium contained KCl at aconcentration of 80 mM, which produces contractions of the colon tissue.The colon tissue was then treated with increasing concentrations of(R)-verapamil, (S)-verapamil, or inactive control, and the resultingreduction in tissue contractions measured. The dihydropyridine calciumantagonist nifedipine was also studied for comparison. Potency wasexpressed as the concentration producing 50% of KCl concentrations(IC₅₀) or as the negative logarithm of the IC₅₀ (pIC₅₀).

[0110] The inactive control reduced contractions in a time-dependentmanner by only about 20% (FIG. 1). In contrast, both (R)- and(S)-verapamil produced more pronounced concentration-dependentrelaxations. The (S)-verapamil (IC₅₀ of 2.95×10⁻⁷) was approximately 3times more potent than the (R)-verapamil (IC₅₀ of 8.51×10⁻⁷) at theconcentrations tested (1-100 μM). (S)-verapamil yielded a pIC50 (−logM)of 6.53±0.13, while that for (R)-verapamil was 6.07±0.16 (n=7 each,P<0.05). Thus, both (R)- and (S)-verapamil were active in the colon,with (S)-verapamil showing a slightly higher potency.

Example 2 Activity of (R)-Verapamil and (S)-Verapamil in the Aorta

[0111] Rat aortic tissue was prepared and mounted in a tissue bath bystandard methods familiar to those skilled in the art. The physiologicalmedium contained KCl at a concentration of 80 mM, which producescontractions of the aortic tissue. The tissue was then treated withincreasing concentrations of (R)-verapamil, (S)-verapamil, or inactivecontrol and the resulting reduction in tissue contractions measured. Thedihydropyridine calcium antagonist nifedipine was also studied forcomparison.

[0112] As shown in FIG. 2, (S)-verapamil (IC₅₀ of 4.78×10⁻⁷) wasapproximately 10 times more potent than (R)-verapamil (IC₅₀ of4.47×10⁻⁶) at relaxing the KCl induced contractions. (S)-verapamilyielded a pIC50 (−logM) of 6.32±0.03, while that for (R)-verapamil wasonly 5.35±0.24 (n=5 each, p<0.05). Thus, (S)-verapamil was significantlymore potent in the aorta than (R)-verapamil. TABLE 1 Potency TissueMeasurement S Isomer R Isomer Nifedipine Colon pIC₅₀ (−log M) 6.53 6.076.97 IC₅₀ (M) 2.95 × 10⁻⁷ 8.51 × 10⁻⁷ 1.07 × 10⁻⁷ Aorta pIC₅₀ (−log M)6.32 5.35 7.61 IC₅₀ (M) 4.78 × 10⁻⁷ 4.47 × 10⁻⁶ 2.45 × 10⁻⁸ IntestinalSelectivity Index 1.62 5.25 0.23 (IC₅₀ Aorta)/(IC₅₀ Colon)

Example 3 Comparison of Relative Potencies of (R)-Verapamil,(S)-Verapamil and Nifedipine

[0113] (R)-verapamil, (S)-verapamil, and Nifedipine all inhibited KClcontractions in rat colon and aorta. While not wishing to be bound byany particular theory, it is possible that these compounds relax the KClcontractions, at least in part, by their calcium channel blockingactivity.

[0114] Table 1 shows the relative potencies of (R)-verapamil,(S)-verapamil, and nifedipine in the aorta and colon. For each compound,a relative intestinal selectivity index was determined by dividing theIC₅₀ observed in the aorta by the IC₅₀ observed in the colon. Anintestinal selectivity index greater than 1.0 indicates that thecompound is more selective for the colon than the aorta. The higher theindex number, the greater the intestinal selectivity. An intestinalselectivity index below 1.0 indicates that the compound is moreselective for the aorta than the colon.

[0115] Nifedipine was significantly more potent in the aorta (IC₅₀ of1.07×10⁻⁷ M; pIC50 of 7.61±0.11, n=7) than in the colon (IC₅₀ of2.45×10⁻⁸ M; pIC50 of 6.97±0.25, n=5). The intestinal selectivity ofnifedipine was 0.23 (1.07×10⁻⁷/2.45×10⁻⁸). Thus, nifedipine wassignificantly more selective for the aorta than for the colon.

[0116] (S)-verapamil was approximately equipotent in the aorta andcolon. The IC₅₀ of (S)-verapamil in the colon was 2.95×10⁻⁷ M; in theaorta, the IC₅₀ was 4.78×10⁻⁷ M. Thus, (S)-verapamil yielded anintestinal selectivity of index of 1.62 (4.78×10⁻⁷/2.95×10⁻⁷). The pIC50values of (S)-verapamil in the colon and aorta were 6.32±0.03 (n=5) and6.53±0.13 (n=7), respectively.

[0117] (R)-verapamil, however, was significantly more potent in thecolon than it was in the aorta. The IC₅₀ of (R)-verapamil in the colonwas 8.51×10⁻⁷ M; in the aorta, the IC₅₀ was 4.78×10⁻⁶ M. Thus,(R)-verapamil yielded a relatively high intestinal selectivity of indexof 5.63 (8.51×10⁻⁷/4.78×10⁻⁷). The pIC50 values of (R)-verapamil in thecolon and aorta were 6.07±0.16 (n=7) and 5.35±0.24 (n=5), respectively.Thus, given the high intestinal selectivity index, (R)-verapamil issignificantly more selective for the intestine than the aorta.

[0118] These results show that (S)-verapamil is not selective for theaorta or colon (i.e., it is about equally active in both tissues), whilenifedipine exhibits significant aortic-selectivity. In contrast,(R)-verapamil (IC₅₀ of 4.47×10⁻⁶) was 10 times less potent in the aortathan (S)-verapamil (IC₅₀ of 4.78×10⁻⁷), but only three times less potentin the intestine (IC₅₀ of 8.51×10-7 for (R)-verapamil; IC₅₀ of 2.95×10⁻⁷for (S)-verapamil). This suggests that the activity of (R)-verapamil isintestinal-selective.

[0119] The consequence of this difference in selectivity is thatadministration of (R)-verapamil can achieve appreciable gastrointestinaleffects while avoiding or reducing the disadvantageous cardiovasculareffects normally associated with administration of (S)-verapamil and theracemic mixture of verapamil. The S isomer, if dosed at similar levels,would likely produce similar gastrointestinal effects, but also greatercardiovascular effects. The significant cardiovascular effects of the Sisomer limits its usefulness in treating, preventing, and/or managingabnormal gastrointestinal motility and intestinal conditions that causethe same. (R)-verapamil, due to its relative intestinal selectivity,overcomes these limitations. As a result, (R)-verapamil can be used totreat, prevent, and/or manage abnormal increases in gastrointestinalmotility, and the intestinal conditions that cause the same, due to itsgreater intestinal-selectivity, while minimizing unwanted cardiovasculareffects.

Example 4 Production of an Instant-Release Tablet Formulation of(R)-Verapamil Using Direct Compression

[0120] Qty % Ingredient FUNCTION (w/w) (R)-VERAPAMIL Active  10.00LACTOSE Diluent  55.78 AVICEL ™ PH101 Dry Binder/  23.52 diluent SODIUMSTARCH Disintegrant  10.00 GLYCOLATE (EXPLOTAB ™) COLLOIDAL Glidant 0.20 SILICON DIOXIDE MAGNESIUM STEARATE Lubricant  0.50 TOTAL 100

[0121] Each of the above-listed ingredients is weighed. The lactose,(R)-verapamil, sodium starch glycolate, colloidal silicon dioxide, andAvicel™, are mixed together in a blender for 15 minutes, untilhomogeneous. The magnesium stearate is added and the composition ismixed for an additional 5 minutes. The resulting mixture is compressedinto oval tablets at a target weight of 400 mg on a suitable tabletmachine.

Example 5 Production of an Instant-Release Tablet Formulation of (R)Verapamil Using Wet Granulation

[0122] Qty % Ingredient FUNCTION (w/w) (R)-VERAPAMIL Active  10.00LACTOSE Diluent  45.28 AVICEL ™ PH101 Dry Binder/  29.02 diluent SODIUMSTARCH Disintegrant  10.00 GLYCOLATE (EXPLOTAB ™) COLLOIDAL Glidant 0.20 SILICON DIOXIDE MAGNESIUM Lubricant  0.50 STEARATE POLYVINYLBinder  5.00 PYRROLIDONE (PVP) *ISOPROPYL ALCOHOL (IPA) Solvent N/ATOTAL 100

[0123] Each of the above-listed ingredients is weighed. The PVP isdissolved in the IPA to form a PVP solution. The (R)-verapamil is mixedwith 50% of the Avicel™ and 50% of the lactose in a suitable mixer(e.g., Planetary (Hobart), High Shear (Diosna/Fielder)) for 15 minutesto produce a homogenous mixture. While continuing to mix, thegranulating fluid (PVP Solution) is added. This composition or mixtureis mixed until a desired granulation end point is achieved (add more IPAif needed to produce a suitable granule). The granules are dried withsuitable drying equipment (e.g., oven or fluidization equipment) untilan acceptable level of moisture (e.g., <1.0%) and IPA (e.g., <0.5%) isachieved.

[0124] The dry granulate is then passed through suitable comminutionequipment (e.g., Co-Mill, Fitzpatrick mill) fitted with a suitable sizedscreen (100-500 micron). The granulate is mixed with the colloidalsilicon dioxide, sodium starch glycolate, and the remainder of thelactose and Avicel™ in a blender for 15 minutes. The magnesium stearateis added, and mixed for an additional 5 minutes. The resulting mixtureis compressed into oval shaped tablets to a target weight of 400 mg on asuitable tablet machine.

Example 6 Production of Modified-Release Tablet Formulations of(R)-Verapamil with Varying Amounts and Grades of Methocel™ Using WetGranulation

[0125] Qty % Qty % Qty % Ingredient FUNCTION (w/w) (w/w) (w/w)(R)-VERAPAMIL Active  30.0  30.00  30.00 LACTOSE Diluent  20.58  10.78 —AVICEL ™ PH101 Dry Binder  23.72  18.52  4.30 diluent METHOCEL ™Controlled  20.00  40.00  60.00 Release Polymer COLLOIDAL Glidant  0.20 0.20  0.20 SILICON DIOXIDE MAGNESIUM Lubricant  0.50  0.50  0.50STEARATE POLYVINYL Binder  5.0  5.0  5.0 PYRROLIDONE (PVP) *ISOPROPYLSolvent N/A N/A N/A ALCOHOL (IPA) TOTAL 100 100 100

[0126] Each of the above-listed ingredients is weighed. The PVP isdissolved in the IPA to form a PVP solution. The (R)-verapamil is mixedwith the Methocel™, 50% of the Avicel™, and 50% of the lactose in asuitable mixer (e.g., Planetary (Hobart), High Shear (Diosna/Fielder))for 15 minutes to produce a homogenous mixture. The Methocel™ can besubstituted with various grades, such as the K and/or E Series, asdescribed by the manufacturer (Dow Chemicals). While continuing to mix,the granulating fluid (PVP Solution) is added. This combination is mixeduntil a desired granulation end point is achieved (add more IPA ifneeded to produce a suitable granule). The granules are dried withsuitable drying equipment (e.g., oven or fluidization equipment) untilan acceptable level of moisture (e.g., <1.0%) and IPA (e.g., <0.5%) isachieved.

[0127] The dry granulate is then passed through suitable comminutionequipment (e.g., Co-Mill, Fitzpatrick mill) fitted with a suitable sizedscreen (100-500 micron). The granulate is mixed with the colloidalsilicon dioxide, sodium starch glycolate, and the remainder of thelactose and Avicel™ in a blender for 15 minutes. The magnesium stearateis added, and the mixture is mixed for an additional 5 minutes. Theresulting mixture is compressed into oval shaped tablets to a targetweight of 400 mg on a suitable tablet machine.

Example 7 Production of Instant-Release Drug Loaded MultiparticulateFormulations of (R)-Verapamil

[0128] Qty Ingredient FUNCTION (mg/g) (R)-VERAPAMIL Active  400.00 NONPAREIL SEEDS Inert carrier  400.00 POLYVINYL Binder  50.00 PYRROLIDONE(PVP) TALC Antiadherent  125.0 COLLOIDAL Glidant  25.00 SILICON DIOXIDEWATER Solvent N/A TOTAL 1000

[0129] The (R)-verapamil, binder, glidant, and antiadherent aredissolved and/or suspended in water. The solution suspension is thensprayed on to the nonpareil seeds using an appropriate fluidized coatingmachine (e.g., Glatt apparatus). After the solution suspension has beenapplied to the nonpareil seeds, the drug-loaded instant-releasemultiparticulates are dried in the fluidized coating machine.

[0130] The drug-loaded instant-release multiparticulates may then beformulated into a suitable dosage form, such as gelatin capsules, and/orfurther processed into a modified-release formulation, as describedbelow. In addition, the drug loaded instant release multiparticulatesmay be used alone, or in combination with the modified-releasemultiparticulates described in Example 8, depending on the releaseprofile that is desired.

Example 8 Production of a Modified-Release Multiparticulate Formulationof (R)-Verapamil

[0131] Instant-release drug-loaded multiparticulates of (R)-verapamilare prepared, as described above. The multiparticulates are then coatedwith polymer solution A or B, as follows, to produce a modified-releasemultiparticulate formulation. Polymer Solution A Batch IngredientFUNCTION (g) EUDRAGIT ™ Controlled 200.00 RS 30D Release Polymer TALCAntiadherent  60.00 TRIETHYL CITRATE Plasticizer  12.00 SIMETHICONEDispersant  1.00 EMULSION WATER Solvent 392.00 TOTAL 665.00

[0132] Polymer Solution B Batch Ingredient FUNCTION (g) EUDRAGIT ™Controlled  900.00 RS 12.5 Release Polymer EUDRAGIT ™ Controlled  300.00RL 12.5 Release Polymer TALC Antiadherent  105.00 DIBUTYL Plasticizer 15.00 SEBECATE MAGNESIUM Antiadherant  30.00 STEARATE ACETONE Solvent 825.00 ISOPROPYL ALCOHOL (IPA) Solvent  825 TOTAL 3000.00

[0133] The above listed ingredients in each table are mixed to producepolymer solutions A and B, respectively. Batch Batch Batch IngredientFUNCTION (g) (g) (g) (R)-VERAPAMIL Active agent 1000 1000 1000Drug-Loaded Instant- with carrier Release and Multiparticulatesexcipients *Polymer Solution Controlled  50  100  200 A or B ReleasePolymer TOTAL 1050 1100 1200

[0134] The drug-loaded instant-release mutiparticulates are placed in asuitable fluidized coating machine (e.g., Glatt apparatus). The polymersolution (polymer solution A or B) is then sprayed onto the drug-loadedinstant-release multiparticulates in the amounts indicated above. Afterthe required amount of polymer solution has been applied, thepolymer-coated multiparticulates are dried in the fluidized coatingmachine. The resulting modified-release multiparticulates areencapsulated into a hard gelatin capsule using an automatedencapsulation machine, in an amount sufficient to produce a 30, 60, 120,240, or 480 mg dose of (R)-verapamil in each capsule.

[0135] Alternatively, the drug-loaded modified-release multiparticulatesmay be mixed with the drug-loaded instant-release multiparticulatesdescribed in Example 7, prior to encapsulation, to vary the rate ofrelease of (R)-verapamil upon administration to a patient.

Example 9 Activity of (R)-Verapamil and (S)-Verapamil in the VasDeferens

[0136] In rat vas deferens there are two components to nervestimulation, an alpha-nonadrenergic component, dominant in theepididymal portion, and a non-adrenergic (purinergic) component,dominant in the prostatic portion. The latter is blocked by nifedipine.A combination of adrenergic blockade and nifedipine virtually abolishesall components. (Brown et al., Br J Pharmacol., 79:379-393, 1983). FIG.3 shows that, in contrast to nifedipine (0.1-10 μM), neither(R)-verapamil nor (S)-verapamil abolished contractions to electricalstimulation in vas prostatic tissue. In the epididymal portion, acombination of alpha adrenergic blockade and nifedipine virtuallyabolishes all components. FIG. 3 shows that high concentrations of both(R)-verapamil and (S)-verapamil reduced this epididymal contraction (inthe presence of nifedipine). (R)- and (S)-verapamil were approximatelyequipotent. Additional, non-stereospecific properties of verapamil mayexplain this action, such as alpha-1-adrenoceptor antagonism orprejunctional inhibition of neurotransmission (see, e.g., Motulsky etal., Circ. Res., 52(2):226-31, 1983.

Example 10 Activity of Other Compounds in the Colon

[0137] Other compounds were tested for their ability to relax the KClcontractions, or block the relaxing action of verapamil. Minoxidil (apotassium channel opener) did not relax the KCl contractions.Glibenclamine (a potassium channel blocker) did not block theverapamil-induced relaxations of the KCl contractions. Prazosin (analpha1-adrenoreceptor antagonist) did not significantly relax KClcontractions. Xylazine (an alpha2-adrenoreceptor agonist) achieved asmall relaxation of the contractions, but only at the highestconcentration tested (10⁻⁴M). Nifedipine (a dihydropyridine calciumantagonist) relaxed the KCl contracted colon tissue with a pIC50 (−logM)of 6.97±0.25 (n=5).

What is claimed is:
 1. A method for treating an abnormal increase ingastrointestinal motility comprising administering a therapeuticallyeffective amount of (R)-verapamil, or a pharmaceutically acceptable saltthereof, substantially purified from its S stereoisomer, to a subject inneed of such treatment.
 2. The method of claim 1, wherein the subject issuffering from irritable bowel syndrome (IBS), an infectious disease ofthe small or large intestine, or symptoms of any of the foregoing. 3.The method of claim 2, wherein the subject is suffering from irritablebowel syndrome.
 4. The method of claim 1, wherein the (R)-verapamil isprovided in a pharmaceutical formulation.
 5. The method of claim 4,wherein the (R)-verapamil formulation is a solid dosage form.
 6. Themethod of claim 4, wherein the (R)-verapamil formulation is administeredorally, nasally, rectally, intravaginally, parenterally, buccally,sublingually or topically.
 7. The method of claim 6, wherein the(R)-verapamil formulation is administered rectally or orally.
 8. Themethod of claim 4, wherein the (R)-verapamil formulation is provided asa tablet, capsule, or suppository.
 9. The method of claim 4, wherein the(R)-verapamil formulation comprises one or more pharmaceuticallyacceptable excipients.
 10. The method of claim 9, wherein the excipientis a starch, sugar, cellulose, diluent, granulating agent, lubricant,binder, disintegrating agent, wetting agent, emulsifier, coloring agent,release agent, coating agent, sweetening agent, flavoring agent,perfuming agent, preservative, antioxidant, plasticizer, gelling agent,thickener, hardener, setting agent, suspending agent, surfactant,humectant, carrier, stabilizer, or a combination thereof.
 11. The methodof claim 1, wherein the (R)-verapamil is administered from one to fivetimes per day.
 12. The method of claim 11, wherein the (R)-verapamil isadministered one time per day.
 13. The method of claim 1, wherein thesubject is a human.
 14. The method of claim 7, wherein the (R)-verapamilis administered orally and the amount of (R)-verapamil ranges from about30 mg to about 600 mg per day.
 15. The method of claim 14, wherein theamount of (R)-verapamil administered ranges from about 60 mg to about480 mg per day.
 16. The method of claim 4, wherein the formulationfurther comprises one or more additional pharmaceutically activecompounds.
 17. The method of claim 1, wherein the (R)-verapamil isadministered in combination with one or more additional pharmaceuticallyactive compounds.
 18. The method of claim 1, wherein the (R)-verapamilis provided in a modified-release formulation.
 19. The method of claim18, wherein the modified-release formulation comprises one or morewater-soluble polymers, water-insoluble polymers, or a combinationthereof.
 21. The method of claim 20, wherein the water-soluble polymeris chosen from polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose,hydroxypropylcellulose, hydroxypropylmethylcellulose, polyethyleneglycol, and mixtures thereof.
 22. The method of claim 20, wherein thewater-insoluble polymer is chosen from ethylcellulose, cellulose acetatecellulose propionate, cellulose acetate propionate, cellulose acetatebutyrate, cellulose acetate phthalate, cellulose triacetate, poly(methylmethacrylate), poly(ethyl methacrylate), poly(butyl methacrylate),poly(isobutyl methacrylate), and poly(hexyl methacrylate), poly(isodecylmethacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate),poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutylacrylate), poly(octadecyl acrylate), poly(ethylene), poly(ethylene) lowdensity, poly(ethylene) high density, poly(ethylene oxide),poly(ethylene terephthalate), poly(vinyl isobutyl ether), poly(vinylacetate), poly(vinyl chloride) or polyurethane, and mixtures thereof.23. The method of claim 18, wherein the modified-release formulation isan osmotic pump dosage form.
 24. The method of claim 18, wherein themodified-release formulation is a matrix system dosage form.
 25. Themethod of claim 18, wherein the modified-release formulation is amembrane controlled dosage form.
 26. The method of claim 18, wherein themodified-release formulation comprises a functional coating.
 27. Themethod of claim 18, wherein the modified-release formulation is providedin the form of a caplet, capsule, bead, granule, particle for suspensionprior to dosing, sachet, or tablet.
 28. A method for preventing anabnormal increase in gastrointestinal motility comprising administeringa therapeutically effective amount of (R)-verapamil, or apharmaceutically acceptable salt thereof, substantially purified fromits S stereoisomer, to a subject in need of such administration.
 29. Amethod for managing an abnormal increase in gastrointestinal motilitycomprising administering a therapeutically effective amount of(R)-verapamil, or a pharmaceutically acceptable salt thereof,substantially purified from its S stereoisomer, to a subject in need ofsuch administration.
 30. A method for reducing an abnormal increase ingastrointestinal motility comprising administering a therapeuticallyeffective amount of (R)-verapamil, or a pharmaceutically acceptable saltthereof, substantially purified from its S stereoisomer, to a subject inneed of such administration.